Treffer: Design of LNA Analogues Using a Combined Density Functional Theory and Molecular Dynamics Approach for RNA Therapeutics.

Title:
Design of LNA Analogues Using a Combined Density Functional Theory and Molecular Dynamics Approach for RNA Therapeutics.
Authors:
Dowerah D; CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784 028, India., V N Uppuladinne M; HPC-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune 411008, India., Sarma PJ; CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784 028, India.; Department of Chemistry, Gargaon College, Sivasagar, Assam 785685, India., Biswakarma N; CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784 028, India., Sonavane UB; HPC-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune 411008, India., Joshi RR; HPC-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune 411008, India., Ray SK; Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur, Assam 784028, India.; Center for Multidisciplinary Research, Tezpur University, Napaam, Sonitpur, Assam 784028, India., Namsa ND; Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur, Assam 784028, India.; Center for Multidisciplinary Research, Tezpur University, Napaam, Sonitpur, Assam 784028, India., Deka RC; CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784 028, India.; Center for Multidisciplinary Research, Tezpur University, Napaam, Sonitpur, Assam 784028, India.
Source:
ACS omega [ACS Omega] 2023 Jun 12; Vol. 8 (25), pp. 22382-22405. Date of Electronic Publication: 2023 Jun 12 (Print Publication: 2023).
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101691658 Publication Model: eCollection Cited Medium: Internet ISSN: 2470-1343 (Electronic) Linking ISSN: 24701343 NLM ISO Abbreviation: ACS Omega Subsets: PubMed not MEDLINE
Imprint Name(s):
Original Publication: Washington, D.C. : American Chemical Society, [2016]-
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Entry Date(s):
Date Created: 20230703 Latest Revision: 20230704
Update Code:
20250114
PubMed Central ID:
PMC10308574
DOI:
10.1021/acsomega.2c07860
PMID:
37396274
Database:
MEDLINE

Weitere Informationen

Antisense therapeutics treat a wide spectrum of diseases, many of which cannot be addressed with the current drug technologies. In the quest to design better antisense oligonucleotide drugs, we propose five novel LNA analogues (A1-A5) for modifying antisense oligonucleotides and establishing each with the five standard nucleic acids: adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). Monomer nucleotides of these modifications were considered for a detailed Density Functional Theory (DFT)-based quantum chemical analysis to determine their molecular-level structural and electronic properties. A detailed MD simulation study was done on a 14-mer ASO (5'-CTTAGCACTGGCCT-3') containing these modifications targeting PTEN mRNA. Results from both molecular- and oligomer-level analysis clearly depicted LNA-level stability of the modifications, the ASO/RNA duplexes maintaining stable Watson-Crick base pairing preferring RNA-mimicking A-form duplexes. Notably, monomer MO isosurfaces for both purines and pyrimidines were majorly distributed on the nucleobase region in modifications A1 and A2 and in the bridging unit in modifications A3, A4, and A5, suggesting that A3/RNA, A4/RNA, and A5/RNA duplexes interact more with the RNase H and solvent environment. Accordingly, solvation of A3/RNA, A4/RNA, and A5/RNA duplexes was higher compared to that of LNA/RNA, A1/RNA, and A2/RNA duplexes. This study has resulted in a successful archetype for creating advantageous nucleic acid modifications tailored for particular needs, fulfilling a useful purpose of designing novel antisense modifications, which may overcome the drawbacks and improve the pharmacokinetics of existing LNA antisense modifications.
(© 2023 The Authors. Published by American Chemical Society.)

The authors declare no competing financial interest.